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Circulating Levels of Endothelial Adhesion Molecules and Risk of Diabetes in an Ethnically Diverse Cohort of Women

¹ Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
² the Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
³ Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts
⁴ Fred Hutchinson Cancer Research Center, Seattle, Washington
⁵ Children's Hospital, Harvard Medical School, Boston, Massachusetts
⁶ Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, Massachusetts
⁷ Department of Public Health Sciences and Epidemiology, John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, Hawaii
⁸ Department of Geriatric Medicine, John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, Hawaii
⁹ Pacific Health Research Institute, Honolulu, Hawaii
¹⁰ HealthPartners Research Foundation, Minneapolis, Minnesota
¹¹ Division of Preventive Medicine, Department of Medicine, School of Medicine, University of Alabama, Birmingham, Alabama
¹² Department of Epidemiology, School of Public Health, University of California, Los Angeles, California
¹³ Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, California

Address correspondence and reprint requests to Dr. Simin Liu, Department of Epidemiology, UCLA School of Public Health, Box 951772, 650 Charles E. Young Dr. South, Los Angeles, CA 90095. E-mail: siminliu{at}ucla.edu

Abbreviations: CRP, C-reactive protein; CVD, cardiovascular disease; HOMA-IR, insulin resistance index estimated using the homeostasis model assessment; ICAM-1, intercellular adhesion molecule-1; VCAM-1, vascular cell adhesion molecule-1

Elevated circulating levels of soluble adhesion molecules as markers of endothelial dysfunction have been related to insulin resistance and its associated metabolic abnormalities. However, their associations with type 2 diabetes remain inconclusive. We conducted a prospective nested case-control study to examine the associations between plasma levels of E-selectin, intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) and diabetes risk among 82,069 initially healthy women aged 50–79 years from the Women's Health Initiative Observational Study. During a median follow-up of 5.9 years, 1,584 incident diabetes case subjects were matched with 2,198 control subjects by age, ethnicity, clinical center, time of blood draw, and follow-up time. Baseline median levels of the biomarkers were each significantly higher among case subjects than among control subjects (E-selectin, 49 vs. 37 ng/ml; ICAM-1, 324 vs. 280 ng/ml; and VCAM-1, 765 vs. 696 ng/ml [all P values <0.001]). After adjustment for risk factors, the relative risks of diabetes among women in the highest quartile versus those in the lowest quartile were 3.46 for E-selectin (95% CI 2.56–4.68; P for trend <0.0001), 2.34 for ICAM-1 (1.75–3.13; P for trend <0.0001), and 1.48 for VCAM-1 (1.07–2.04; P for trend = 0.009). E-selectin and ICAM-1 remain significant in each ethnic group. In conclusion, higher levels of E-selectin and ICAM-1 were consistently associated with increased diabetes risk in a multiethnic cohort of U.S. postmenopausal women, implicating an etiological role of endothelial dysfunction in the pathogenesis of type 2 diabetes.

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